Is TYK2 p.Pro441Arg (c.1322C>G) pathogenic?

TYK2 p.Pro441Arg (c.1322C>G) is classified Uncertain significance in TYK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-24). AlphaMissense: likely benign (0.2642); Very rare (popmax 0.00669%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TYK2 p.Pro441Arg (c.1322C>G)?

TYK2 p.Pro441Arg (c.1322C>G) is associated with Inborn genetic diseases, immunodeficiency 35 (ClinVar).

How common is TYK2 p.Pro441Arg (c.1322C>G) in the general population?

TYK2 p.Pro441Arg (c.1322C>G) is very rare (popmax 0.00669%, nfe) (gnomAD).

What do computational predictors say about TYK2 p.Pro441Arg (c.1322C>G)?

AlphaMissense predicts likely benign (score 0.2642) — an in-silico prediction, not a clinical call.

TYK2 p.Pro441Arg

c.1322C>G · rs770604675 · VCV1352236

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2642	likely benign
REVEL	0.695	pathogenic-leaning
SaProt	LLR -11.40	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 6.7e-09 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% European (non-Finnish) · 79/1,179,988 alleles

Filtering AF 0.00546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.00554% 81/1,461,594 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00669%	14,937
East Asian	0.00223%	44,882
African / African-American	0.00133%	75,060

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TYK2
Protein: p.Pro441Arg
Coding: c.1322C>G
MANE Select: NM_003331
dbSNP: rs770604675
Type: single nucleotide variant
Location: chr19:10364659 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.69 · 52 PDB
Residue 441: an α-helix

Full TYK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: immunodeficiency 35

Similar variants

TYK2 p.Arg609Ter Pathogenic/Likely pathogenic ★★ same condition
TYK2 p.Trp798Ter Pathogenic ★★ same condition
TYK2 p.Ala1004Gly Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala1026Thr Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala165Thr Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala195Ser Uncertain significance ★★ ⚠ same condition
TYK2 p.Ala195Thr Uncertain significance ★★ same condition
TYK2 p.Ala413Val Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tyk2-p-pro441arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown